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WO2022028346A1 - Composé aromatique et son application dans un médicament antitumoral - Google Patents

Composé aromatique et son application dans un médicament antitumoral Download PDF

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WO2022028346A1
WO2022028346A1 PCT/CN2021/109963 CN2021109963W WO2022028346A1 WO 2022028346 A1 WO2022028346 A1 WO 2022028346A1 CN 2021109963 W CN2021109963 W CN 2021109963W WO 2022028346 A1 WO2022028346 A1 WO 2022028346A1
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deuterium
hydrogen
compound
reaction
pharmaceutically acceptable
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PCT/CN2021/109963
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English (en)
Chinese (zh)
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张强
杜锋田
王海波
郭娜
张涛
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上海喆邺生物科技有限公司
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Priority to CN202180012413.XA priority Critical patent/CN115052870B/zh
Priority to JP2022579084A priority patent/JP7584815B2/ja
Priority to EP21854249.6A priority patent/EP4194452A4/fr
Publication of WO2022028346A1 publication Critical patent/WO2022028346A1/fr
Priority to US18/157,397 priority patent/US20230159529A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an aromatic compound, a preparation method thereof, and the application of the aromatic compound in medicine for treating diseases.
  • Aromatic rings as a common structural unit in the chemical design of pharmaceuticals, widely exist in the molecular structure of drugs, and play an important role in improving the hydrophilic and hydrophobic properties of drug molecules.
  • the introduction of other functional groups on the aromatic ring to form a large ⁇ bond can effectively control the density of the rich electron cloud on the aromatic ring, affect the effective chimerization of the aromatic ring and the amino acid residues of the drug target protein, and improve the relationship between the drug molecule and the amino acid residue.
  • the efficacy of the target protein regulating the ability of the drug molecule to agonize or inhibit the target protein.
  • aromatic rings include carbonyl compounds (aldehydes, ketones, carboxylic acids and carboxylic acid-derived groups, etc.), unsaturated alkanes (alkenes, alkynes, etc.).
  • the following listed drugs, or the molecular structures of candidate drugs in clinical stage introduce other functional groups (such as carbonyls, unsaturated alkanes, etc.) on the aromatic ring to improve the drug-like properties of drug molecules and improve drug efficacy, The reduction of toxic and side effects has achieved ideal results.
  • the present invention provides a compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • U is nitrogen atom or CR U , wherein RU is hydrogen or deuterium;
  • M is an oxygen atom, or a sulfur atom
  • X is nitrogen atom or CR 1
  • Y is nitrogen atom or CR 2
  • Z is nitrogen atom or CR 3 ;
  • E is nitrogen atom or CR 11
  • W is nitrogen atom or CR 12
  • G is nitrogen atom or CR 13
  • J is nitrogen atom or CR 14 ;
  • R a , R b are each independently hydrogen, deuterium, halogen
  • R d , R e are each independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxyl, amino, sulfone, sulfonamido, carbonamido, alkenyl, alkynyl ;
  • Ring A is a 5- to 7-membered nitrogen-containing heterocyclic group
  • R 1 , R 2 , R 3 , R 11 , R 12 , R 13 , R 14 , R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 17g , R 17h are each independently selected from hydrogen , deuterium, halogen, alkyl, deuterated alkyl;
  • R 15a is hydrogen, deuterium
  • Q is -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -;
  • T is oxygen atom, sulfur atom
  • L is alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, chloroalkene, haloalkyl.
  • the present invention provides the compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • Ring A is selected from the following groups:
  • the present invention provides a compound of formula (II), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • X is nitrogen atom or CR 4
  • Y is nitrogen atom or CR 5
  • U is nitrogen atom or CR U , wherein RU is hydrogen or deuterium;
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 3a , R 3b , R 3c , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl;
  • R 15a is hydrogen, deuterium
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h are each independently selected from hydrogen, deuterium, methyl, trideuteromethyl;
  • R 7 is fluorine, chlorine
  • R 8 , R 9 , R 10 are each independently selected from hydrogen, deuterium, and fluorine;
  • the present invention provides a compound of formula (III), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • X is nitrogen atom or CR 4
  • Y is nitrogen atom or CR 5
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 3a , R 3b , R 3c , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 each independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl;
  • R 15a is hydrogen, deuterium
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h are each independently selected from hydrogen, deuterium, methyl, trideuteromethyl;
  • R 7 is fluorine, chlorine
  • R 8 , R 9 , R 10 are each independently selected from hydrogen, deuterium, and fluorine;
  • the present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
  • the present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
  • the present invention provides the following compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts,
  • the present invention provides the following compounds, their stereoisomers, their tautomers, pharmaceutically acceptable salts,
  • the present invention provides a compound of formula (IIIM), its stereoisomer, its tautomer or a pharmaceutically acceptable salt,
  • the axial chiral stereo configuration formed by the connection between the 1-position nitrogen atom of ring E and the 1'-position carbon atom of ring F is optically pure;
  • X is a nitrogen atom or CR 4
  • Y is a nitrogen atom or CR 5
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 3a , R 3b , R 3c , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl;
  • R 15a is hydrogen, deuterium
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h are each independently selected from hydrogen, deuterium, methyl, trideuteromethyl;
  • R 7 is fluorine, chlorine
  • R 8 , R 9 , R 10 are each independently selected from hydrogen, deuterium, and fluorine;
  • the present invention provides a compound of formula (IIIM-1), its stereoisomer, its tautomer or pharmaceutically acceptable salt,
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 11 , R 12 , R 13 , R 14 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkane base;
  • R 15a is hydrogen, deuterium
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h are each independently selected from hydrogen, deuterium, methyl, trideuteromethyl;
  • R 7 is fluorine, chlorine
  • R 8 , R 9 , R 10 are each independently selected from hydrogen, deuterium, and fluorine;
  • R 17 is hydrogen, deuterium, methyl, ethyl, deuterated methyl, deuterated ethyl; wherein, the structural fragment
  • the present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
  • the present invention provides the following compounds whose axial chiral stereoconfiguration is R configuration, tautomer, pharmaceutically acceptable salt,
  • the present invention provides the following compounds whose axial chiral stereoconfiguration is R configuration, their tautomers, pharmaceutically acceptable salts,
  • the present invention provides the following compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds of the present invention or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention provides a compound according to the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the present invention for the prevention and/or treatment of cancer associated with KRAS G12C, HRAS or NRAS mutation mediated
  • the use in the medicine of disease, the use includes the compound of any one of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition according to the present invention can be used alone, or in combination with other drugs including immunotherapy Therapeutic methods are used in combination to prevent and/or treat diseases associated with KRAS, HRAS or NRAS mutation-mediated cancers.
  • liver cancer esophageal cancer
  • gastric cancer renal cell cancer
  • sarcoma cholangiocarcinoma
  • colon cancer prostate cancer
  • ovarian cancer breast cancer
  • pancreatic cancer MYH-related polyposis
  • colorectal cancer or lung cancer.
  • Figure 1 shows the single crystal diffraction results of intermediate 3M.
  • halogen refers herein to -F, -Cl, -Br and -I.
  • fluoro refers herein to -F.
  • chlorine refers herein to -Cl.
  • bromine refers herein to -Br.
  • cyano refers herein to -CN.
  • amino refers herein to -NH2 .
  • hydroxyl refers herein to -OH.
  • alkyl refers herein to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and the term includes straight and branched chain hydrocarbon groups.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like.
  • alkyl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl , acyloxy, oxo, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy aryl, aryloxy, heteroaryloxy, aryl or heteroaryl.
  • aryl refers to a 6 to 10 membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups, polycyclic (ie, with a conjugated pi electron system) group. A ring) group with adjacent pairs of carbon atoms. Aryl groups can be covalently attached to the defined chemical structure at any carbon atom that results in a stable structure.
  • Aryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide group, ester group, amino group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • heteroaryl refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O or S and the like.
  • the term can have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran , indole, isoindole, etc.), where the fused ring may or may not be an aromatic group containing a heteroatom, assuming that the point of attachment is through an atom of the aromatic heteroaryl group.
  • heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy group, amide group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • alkenyl refers herein to an alkenyl group having from 2 to 8 carbon atoms and having at least one site of alkenyl unsaturation.
  • alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like.
  • alkenyl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl , amide group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, cycloalkoxy group, mercapto group, alkyl mercapto group, deuterated alkyl mercapto group, sulfone group, Sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.
  • substituents deuterium, fluorine, chlorine, bromine, iodine, cyano,
  • alkynyl refers herein to an alkyl group in which two adjacent carbon atoms are joined by a triple bond, wherein the alkyl group is as defined herein.
  • Alkynyl means an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy , carboxyl, amino, alkyl, alkoxy, acyl, amido, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, Alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, aryl Alkyl, ester group.
  • heterocyclyl refers to a substituted or unsubstituted saturated or unsaturated aromatic, non-aromatic ring containing at least 1 to 5 heteroatoms selected from N, O or S.
  • Aromatic ring, non-aromatic ring can be 3- to 10-membered monocyclic, 4- to 20-membered spiro ring, and ring or bridged ring, optionally substituted N, S in heterocyclyl ring can be oxidized to various oxidation states .
  • a 3- to 12-membered heterocycle is preferred.
  • Non-limiting examples include oxiranyl, oxetanyl, oxolanyl, oxanyl, oxanyl, oxetyl, aziridinyl, azetidine Base, Azacyclopentyl, Azacyclohexyl, Azacyclopentyl, 1,3-Dioxopentyl, 1,4-Dioxopentyl, 1,3-Dioxopentyl, 1 ,3-dioxohexyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furanyl, thienyl, pyrrolyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyr
  • haloalkyl refers to an alkyl group in which "alkyl” as defined above is substituted with a halogen. Wherein halogen includes. Fluorine, chlorine, bromine, iodine, etc.
  • alkenylalkyl refers to an alkyl group in which "alkyl” as defined above is substituted with “alkenyl” as defined above.
  • alkynylalkyl refers to an alkyl group in which "alkyl” as defined above is substituted with “alkynyl” as defined above.
  • nitrogen-containing heterocyclyl refers to a ring system containing a nitrogen atom, which may be "parallel combination" of aromatic and non-aromatic ring systems, or linked to other ring systems through “spirocarbon atoms”, such as the following structures:
  • amide includes C-amide groups and N-amide groups, ie, -C(O)NR A R B and -NR A C(O) RB groups, respectively.
  • R A and R B are independently hydrogen as defined herein or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle base.
  • Amide groups thus include, but are not limited to, carbamoyl groups (-C(O) NH2 ) and carboxamide groups (-NHC(O)H).
  • the amide is -NR A C(O)-(C 1-5 alkyl), which is referred to as “carbonylamino", in other embodiments, the amide is -NHC(O) -Alkyl, this group is called “alkanoylamino”.
  • sulfonamide includes S -sulfonamide groups and N - sulfonamide groups, ie, -SO2NRCRD and -NRCSO2RD groups , respectively.
  • R C and R D are independently hydrogen as defined herein or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle base.
  • Sulfonamide groups thus include, but are not limited to, sulfonyl ( -SO2NH2 ) .
  • the sulfonamide is -NHSO2 - alkyl, which is referred to as "alkylsulfonylamino".
  • the present invention also includes isotopically labeled compounds of the present invention, ie, having the same structure as disclosed above, but in which one or more atoms are replaced by an atom having the same number of protons but a different number of neutrons.
  • isotopes that are incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I, etc.
  • the compounds of the present invention are within the scope of the present invention.
  • Certain isotopically-labeled compounds of the invention such as those labeled with3H or14C , are useful in drug tissue distribution assays, therefore, 3H or14C isotopes are particularly preferred for their ease of preparation and detection.
  • Certain compounds of the present invention that are replaced by heavier isotopes such as 2 H, 18 O have certain therapeutic advantages due to better metabolic stability, such as increased in vivo half-life and lower doses and other comprehensive properties, therefore, 2 H, 18 O is also preferred in some cases.
  • the compounds provided by the present invention can be prepared by standard synthetic methods well known in the art, and this specification provides general methods for preparing the compounds of the present invention. Starting materials are generally commercially available or prepared by methods well known to those skilled in the art.
  • nucleophilic substitution reaction with SM2 is carried out to obtain M1
  • a reaction with SM-3 is carried out to obtain M2
  • the protective group is removed to obtain M3 and then further reaction is carried out to obtain compound II.
  • the concentrate was slurried with ethyl acetate and n-hexane, allowed to stand, filtered, and the filter cake was washed with n-hexane and dried. After the filtrate was concentrated, it was purified by silica gel column chromatography to obtain 38 g of white solid.
  • the product of the previous step was added to a 1000ml three-necked flask, and a solution of oxalyl chloride (18.5ml) in dichloromethane (20ml) was added dropwise at 0°C. After dropping, the temperature was raised to 75°C and stirred. Concentrate to dryness under reduced pressure, cool to 0°C, add tetrahydrofuran (300ml), dropwise add a solution of 2-isopropyl-4-methylpyridin-3-amine (28.7g) in tetrahydrofuran (150ml), keep stirring at 0°C .
  • reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure until a solid precipitated out, cooled to 0 °C, and kept for 15 minutes. After filtration, the filter cake was washed with ethyl acetate and petroleum ether, and dried; the filtrate was purified by silica gel column chromatography to obtain 51 g of white solid.
  • reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure until a solid precipitated out, cooled to 0 °C, and kept for 30 minutes. After filtration, the filter cake was washed with ethyl acetate and petroleum ether, and dried; the filtrate was concentrated and purified by silica gel column chromatography to obtain 38 g of a light yellow solid in total.
  • reaction was slowly poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography to obtain 2 g of a yellow solid.
  • reaction was slowly poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 23.5 g of a yellow solid.
  • reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.45 g of an off-white solid.
  • reaction solution was added to saturated ammonium chloride solution for quenching, extracted with ethyl acetate, and the organic phases were combined; the organic phase was cooled, 0.5M aqueous hydrochloric acid solution (8L) was slowly added first, then 1.0M aqueous hydrochloric acid solution (2L) was added, and the temperature was kept stirring. . Separation, washed four times with saturated brine, dried over anhydrous sodium sulfate for 30 minutes; concentrated to dryness, added petroleum ether (3.75L) to cool down and stirred, filtered, the filter cake was rinsed with petroleum ether, and the filter cake was placed in a drum at 40°C Air-dried, 1.9kg was obtained.
  • X2 is obtained through chemical reaction conversion (reference US20190374542).
  • the specific preparation method is as follows:
  • Compound A (prepared according to WO2020050890, WO2019051291) was weighed 5.00g into a 250mL round-bottomed flask, 50mL of methyltetrahydrofuran was added, and under nitrogen protection, stirred at 75°C for 30min, until it was completely dissolved into a clear solution, 10g of dissolved (+)-DBTA in 20 mL of methyltetrahydrofuran, after mixing the above two methyltetrahydrofuran solutions, continue to add 50 mL of n-heptane dropwise at 75 °C, and then continue to stir the above mixture at 25 °C for 8 After 1 hour, the solid was filtered, and dried by blowing at 50° C.
  • the intermediate 22 was prepared by the method of reference. (References Journal of Biosciences (Bangalore, India) (2009), 34(1), 21-26; JP61282089; US20030148480, etc.).
  • the specific preparation method is as follows:
  • reaction solution was slowly added to ice water, extracted once with ethyl acetate, the organic phase was discarded, the pH of the aqueous phase was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate, and the organic phases were combined, It was washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 1.6 g of a yellow solid.
  • the product was dissolved in dichloromethane, N,N-diisopropylethylamine was added, the temperature was lowered to a low temperature under nitrogen protection, and the dichloromethane solution of 18 O-acryloyl chloride was slowly added dropwise, and the solution was stirred at room temperature. After the reaction was completed, poured into aqueous ammonium chloride solution, extracted with ethyl acetate, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product molecule.
  • the raw material intermediate, 2-formylbenzeneboronic acid, potassium acetate, 1,4-dioxane, water and palladium catalyst were added into a three-necked flask, and after nitrogen replacement 3 times, the temperature was gradually increased and stirred.
  • the product was dissolved in dichloromethane, N,N-diisopropylethylamine was added, the temperature was lowered under nitrogen protection, and the dichloromethane solution of 18 O-acryloyl chloride was slowly added dropwise.
  • the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate and combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the product.
  • the product was dissolved in dichloromethane, N,N-diisopropylethylamine was added, the temperature was lowered under nitrogen protection, and the dichloromethane solution of 18 O-acryloyl chloride was slowly added dropwise. After the drop was completed, the reaction was stirred at room temperature. The solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a pale yellow solid.
  • reaction solution was concentrated to dryness, dichloromethane (7ml), N,N-diisopropylethylamine (882mg) were added to the residue, the temperature was lowered to 0°C under nitrogen protection, and acryloyl chloride ( 124mg) in dichloromethane (0.5ml), the dropwise addition was completed, stirred at room temperature, the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate three times, the organic layers were combined, washed once with saturated brine, Dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain 600 mg of pale yellow solid.
  • reaction solution was poured into aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography. A pale yellow solid was obtained.
  • the compound 3-7MIS was prepared by using the intermediate 3M as the raw material.
  • Rf: 0.50 (CH 2 Cl 2 :MeOH 10:1).
  • the specific preparation method is as follows:
  • reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain a yellow solid.
  • the product was dissolved in dichloromethane, N,N-diisopropylethylamine was added, the temperature was lowered to 0°C under nitrogen protection, and the dichloromethane solution of acryloyl chloride was slowly added dropwise. After dropping, the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a pale yellow solid.
  • the product was dissolved in dichloromethane, N,N-diisopropylethylamine was added, the temperature was lowered to 0°C under nitrogen protection, and the dichloromethane solution of acryloyl chloride was slowly added dropwise. After dropping, the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried, filtered, concentrated, and purified by silica gel column chromatography to obtain a solid product.
  • the product was dissolved in dichloromethane, N,N-diisopropylethylamine was added, the temperature was lowered under nitrogen protection, and the dichloromethane solution of acryloyl chloride was slowly added dropwise. After the drop was completed, the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a pale yellow solid.
  • the specific preparation method is as follows:
  • the raw material (876 mg) and dichloromethane (10 ml) were added to a 50 ml single-necked bottle, nitrogen was replaced, trifluoroacetic acid (4.7 g) was slowly added dropwise under an ice bath, the temperature was raised to 30° C., and stirred for 30 minutes. After the reaction was completed, it was concentrated to stop flow, dichloromethane (10 ml) was added, DIPEA (1.1 g) and acryloyl chloride (188 mg) were slowly added dropwise under ice bath, the temperature was raised to 30° C. and stirred for 20 minutes.
  • the product of the previous step (860 mg) and dichloromethane (10 ml) were added to a 50 ml single-necked bottle, nitrogen was replaced, trifluoroacetic acid (2 ml) was slowly added dropwise under an ice bath, and the temperature was raised to 30° C. and stirred for 30 minutes.
  • the reaction was completed, concentrated to dryness, added dichloromethane (10ml) to dissolve, water and an appropriate amount of saturated sodium carbonate aqueous solution to adjust the pH of the aqueous phase to 7-8, extracted with dichloromethane, combined organic layers, washed once with saturated brine, anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate to dryness to give 707 mg of a brown solid.
  • reaction was completed, quenched by adding saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 340 mg of white solid.
  • This step “carbon-carbon bond construction” Suzuki reaction is the core step in the manufacture of AMG510. Its reaction efficiency and reaction specificity are related to the formation and control strategy of impurities in AMG510.
  • This step Suzuki reaction has three key technical points: ( 1) the catalyst used in the Suzuki reaction; (2) the temperature of the Suzuki reaction; (3) the raw material used in the Suzuki reaction.
  • the preparation of the compound of the present invention uses the raw material of Suzuki reaction (aromatic boronic acid raw material, namely compound BOH), and the raw material used in AMG510 (aromatic potassium fluoroborate raw material, namely compound BFK).
  • compound BFK needs to be prepared in advance by the following method (recorded on page 72 of WO2020102730A1):
  • the Suzuki reaction step in the synthesis of the compound of the present invention has more advantages in industrial application than the similar preparation steps of AMG510.
  • MIA PaCa-2 cells in exponential growth phase were digested with trypsin-EDTA, plated in 96-well plates at 2000-3000 cells per well, and cultured overnight at 37°C under 5% CO 2 conditions.
  • the test compound was prepared into a stock solution with DMSO, diluted with DMEM growth medium, added to a 96-well plate, and incubated in an incubator at 37°C under 5% CO 2 for 72 hours. After the incubation, an equal volume of CellTiter -Glo detection reagent was added to each well, incubated after shaking, and the chemiluminescence value was measured with a microplate reader.
  • A stands for IC 50 value (nM) ⁇ 50;
  • B stands for IC 50 value (nM) 50 ⁇ 150 (excluding 150);
  • C stands for IC 50 value (nM) 150 ⁇ 300;
  • D Represents IC 50 value (nM)>300;
  • cytostatic activities of some representative compounds of the present invention are as follows:
  • NCI-H358 cells in exponential growth phase were digested with trypsin-EDTA, plated at 2000-3000 cells per well in a 96-well plate, and cultured at 37°C under 5% CO 2 overnight.
  • the test compounds were prepared into a stock solution with DMSO, serially diluted with RPMI 1640 growth medium, added to a 96-well plate, and incubated in an incubator at 37°C under 5% CO 2 for 72 hours. After the incubation, an equal volume of CellTiter -Glo detection reagent was added to each well, incubated after shaking, and the chemiluminescence value was measured with a microplate reader.
  • A represents an IC50 value (nM) less than or equal to 50
  • B represents an IC50 value (nM) greater than 50
  • the cell proliferation inhibitory activity of H358 is significantly better than its corresponding axial chiral S configuration compound 3-2P; the cell proliferation inhibitory activity of R configuration compound 3-2M is Its corresponding axial chiral S configuration compound 3-2P is more than 5 times.
  • Compound 3-6M with axial chiral R configuration has significantly better inhibitory activity on H358 than its corresponding axial chiral S configuration compound 3-6P.
  • A represents IC50 value (nM) less than 50
  • B represents IC50 value (nM) greater than 50
  • Test samples compound 3-2M, compound 3-6M.
  • Dosing frequency once a day for 3 days.
  • Test sample compound 3-2M, compound 3-6M;
  • Test group blank solvent control group; compound 3-2M (10 mg/kg, QD ⁇ 15 days), compound 3-6M (10 mg/kg, QD ⁇ 15 days);
  • MIA-paca-2 cells were cultured in vitro, subcutaneously inoculated into the right back of nude mice, and the tumor-bearing nude mice were randomly divided into groups. Subsequently, each group of animals was dosed, and the day of the first dose was defined as the first day of the experiment;
  • observation time and frequency once a day
  • observation index or content including but not limited to animal administration parts, appearance signs, general behavioral activities, mental state, death and other abnormal manifestations. Animals were euthanized after the experiment.
  • the tumor inhibitory efficacy of the compounds was evaluated by the tumor growth inhibition rate TGI (%).
  • TGI(%) [1-(average tumor volume at the end of treatment group-average tumor volume at the beginning of treatment group)/(average tumor volume at the end of control group administration-average tumor volume at the beginning of control group administration )] ⁇ 100%.
  • Compound 3-2M and Compound 3-6M have significant inhibitory effects on the growth of pancreatic cancer MIA-paca-2 cells subcutaneously transplanted in nude mice;
  • Test method Langendorff in vitro perfused heart tested the effect of compounds on electrocardiogram.
  • the test method used in this experiment is as follows:
  • A represents a reduction in heart rate of less than 5%
  • B means that the heart rate decreases by more than or equal to 5% and less than 15%;
  • C represents a reduction in heart rate greater than or equal to 15%
  • A represents IC50 value (nM) ⁇ 50;
  • B represents IC50 value (nM) 50 ⁇ 150;
  • C represents IC50 value (nM)>150;
  • Test samples compound 3-2M, compound 3-16M, TM-1, TM-3, AMG510 (purchased);
  • Test group blank solvent control group; compound 3-2M (100 mg/kg, QD ⁇ 15 days), compound 3-16M (100 mg/kg, QD ⁇ 15 days); TM-1 (100 mg/kg, QD ⁇ 15 days) days); TM-3 (100 mg/kg, QD ⁇ 15 days); AMG510 (100 mg/kg, QD ⁇ 15 days);
  • NCI-H358 tumor cells in logarithmic growth phase were cultured and collected in vitro, and subcutaneously inoculated into the right back of nude mice at 5 ⁇ 10 6 cells/cell.
  • tumor volume grew to 150-300 mm 3 Tumor-bearing nude mice were randomized.
  • each group of animals was dosed, and the day of the first dose was defined as the first day of the experiment;
  • observation time and frequency once a day
  • observation index or content including but not limited to animal administration parts, appearance signs, general behavioral activities, mental state, death and other abnormal manifestations. Animals were euthanized after the experiment.
  • the tumor inhibitory efficacy of the compounds was evaluated by the tumor growth inhibition rate TGI (%).
  • TGI(%) [1-(average tumor volume at the end of treatment group-average tumor volume at the beginning of treatment group)/(average tumor volume at the end of control group administration-average tumor volume at the beginning of control group administration )] ⁇ 100%.
  • Compound 3-2M and Compound 3-16M have a significant inhibitory effect on the growth of lung cancer NCI-H358 cells subcutaneously transplanted in nude mice, and Compound 3-2M and Compound 3-16M at a dose of 100 mg/kg, The tumor inhibition effect was better than that of AMG510, TM-1 and TM-3.
  • the cells were cultured in a carbon dioxide incubator; during the period, the drug-containing medium was replaced to observe the cell growth; after the incubation, the cells were stained with NBT, and the number of cell colonies was counted, and the IC 50 value of the compound inhibiting cell proliferation was obtained.
  • Compound 3-2M and compound 3-16M showed significant anti-cell proliferation activity against KRAS G12C mutant cell NCI-H358, and its inhibitory activity was better than AMG510.
  • test solutions Solutions of test compounds 3-16M were routinely sonicated and shaken to ensure complete dissolution of the compounds.
  • Cell culture The cell line was derived from HEK-293 cells overexpressing hERG potassium channel. Cells were cultured in a 37°C, 5% CO2 incubator, and when the cell density reached 80% of the dish, pre-washed with phosphate buffered saline (PBS), then digested with trypsin/EDTA, and stopped by adding cell culture medium Digest, gently pipette the cells and transfer to a centrifuge tube, centrifuge at 1000 rpm, pour off the supernatant, add cell culture medium, mix the cells by gently pipetting, and then transfer to a petri dish for passage Incubate, or drop cells on a circular glass slide and place them in a petri dish to allow the cells to adhere for experiments.
  • PBS phosphate buffered saline
  • Electrophysiological manual patch clamp system experiments by calculating the hERG IC50 values of the compounds, are as follows:
  • Compound 3-16M has no blocking effect on hERG potassium channel in the tested concentration range (IC50>100 ⁇ M).
  • the literature (The New England Journal of Medicine, 2020; 383: 1207-1217; DOI: 10.1056/NEJMoa1917239) appendix supporting information (page 23), which records the IC50 value of AMG510 for hERG of 54.8 ⁇ M.
  • the potential cardiac safety of compound 3-16M is better than that of AMG510.
  • the safety test of continuous administration revealed that in the three-day continuous administration test of compound 3-2M and compound 3-6M, the dose was gradually increased from 400 mg/kg to 800 mg/kg, and the animals in all dose groups had normal water and food intake and normal activities. The body weight was normal, and there were no obvious abnormalities.
  • Test samples compound 3-29; compound 3-16M; compound 3-32.
  • Dosing frequency once a day for 14 days.
  • the dried granules are sieved with a swing granulator, and the granulated granules are weighed.
  • the granulated granules are added to the three-dimensional multi-directional motion mixer, and after the mixing is completed, magnesium stearate is added, and the total mixed granules are obtained.
  • the mixed granules are filled into No. 1 gelatin hollow capsules, and qualified capsules are screened out to prepare capsules to be packaged.
  • a capsule sample with neat appearance was obtained, and the content uniformity of the capsule product met the requirements (A+2.2S ⁇ 15); in the dissolution medium with pH 2.0, the cumulative dissolution rate within 1 hour was greater than 75%.

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Abstract

L'invention concerne un inhibiteur de protéine composite aromatique, un stéréoisomère, un tautomère, ou un sel pharmaceutiquement acceptable de celui-ci, un procédé associé à la préparation et l'utilisation du composé, une composition pharmaceutique comprenant le composé, et un procédé pertinent de traitement du cancer. Le composé aromatique présente une activité inhibitrice sélective et significative sur une protéine, et a une large perspective d'application dans le domaine du traitement des tumeurs.
PCT/CN2021/109963 2020-08-02 2021-08-02 Composé aromatique et son application dans un médicament antitumoral WO2022028346A1 (fr)

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WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
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US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
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US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
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US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
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WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras

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